Involvement of Notch in Activation and Effector Functions of γδ T cells

Notch signaling plays a pivotal role in cell fate decision and lineage commitment of lymphocytes. Although the role of Notch in CD4(+) and CD8(+) alpha beta T cells is well documented, there are no reports on how Notch signaling regulates effector functions of gamma delta T cells. gamma delta T cells are a minor fraction in the peripheral blood but are known to play a major role in defense against pathogens and tumors. In this study, we show that Notch receptors (mRNA and protein) are expressed in peripheral gamma delta T cells. Inhibition of Notch signaling by gamma-secretase inhibitor inhibited the proliferation and IFN-gamma secretion of gamma delta T cells in response to stimulation with phosphoantigens and anti-CD3 mAb. In the presence of gamma-secretase inhibitor, the antitumor cytolytic ability of gamma delta T cells was inhibited with a decreased CD107a expression. Knockdown of Notch1 and Notch2 genes in gamma delta T cells using small interfering RNA inhibited their antitumor cytotoxic potential. Our study describes for the first time, to our knowledge, the role of Notch as an additional signal contributing to Ag-specific effector functions of gamma delta T cells.